Within the realm of drug design, the stereospecific incorporation of fluorine substituents is a powerful and widely employed tactic to circumvent metabolism issues arising from in vivo C—H bond oxidation. On this basis, the catalytic production of carbon-fluorine stereogenicity has become a methodological goal of central importance to practitioners of chemical and pharmaceutical synthesis. Surprisingly, however, catalytic methods for the asymmetric construction of C—F bonds are rare, the majority involving α-substituted β-keto ester substrates that are structurally precluded from product epimerization (see Hamashima et al. (2005) Tetrahedron Lett. 46:1447; Shibara et al. (2004) Snylett. 1703; Ma et al. (2004) Tetrahedron Asym. 1007; Kim (2002) Org. Lett. 4:545). Alpha-fluoro aldehydes have been generally recognized as unstable compounds, insofar as decomposition is often noted upon purification, e.g., using column purification or distillation. See, e.g., Purrington et al. (1986) Tet. Lett. 27:2715-16. In addition, methods for halogenating aldehydes and ketones with bromine, chlorine, and iodine are not successful when fluorine is used.
There is, accordingly, a need in the art for an improved enantioselective fluorination method. An ideal method would enable rapid and enantiocontrolled C—F bond formation using stable, inexpensive reagents and catalysts that are inert to product epimerization and readily allow the fluorinated compound to be further functionalized.